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Retatrutide-Diabetes
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What is the mechanism of action of retatrutide?
Retatrutide activates GIP, GLP-1, and glucagon receptors. Preclinical and early-phase clinical data suggests retatrutide may reduce food intake; enhance energy expenditure; improve lipid metabolism and glucose homeostasis; and reduce inflammation.
Content Overview
How Does Food Intake Stimulate GLP-1, GIP, and Glucagon?
In healthy individuals, food intake initiates a series of physiological responses that help regulate blood glucose levels and appetite.1-4 Glucagon-like peptide -1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon are 3 nutrient-stimulated hormones involved in this physiological response. Each of these 3 hormones exerts distinct effects while also working collectively to modulate overlapping physiological processes.1,2,4
Impairments of these physiological responses may contribute to the development of metabolic disorders, such as obesity or type 2 diabetes.1,2,4
Role of GLP-1
Role of GIP
How Does Retatrutide Work?
Retatrutide is a novel synthetic molecule, which is an agonist of the
- GIP receptor
- GLP-1 receptor, and
- glucagon receptor.6
Structurally, retatrutide is an amino acid sequence including a C20 fatty diacid moiety that enables albumin binding and prolongs the half-life.6,7
The half-life is approximately 6 days. This, combined with achievement of time to maximum concentration (Tmax) within 12 to 72 hours of dosing, supports once-weekly subcutaneous dosing.6,7
In vitro, retatrutide shows
- 8.9-fold greater potency than human GIP at the human GIP receptor
- 2.5-fold less potency than human GLP-1 at the human GLP-1 receptor, and
- 2.9-fold less potency than human glucagon at the human glucagon receptor.6,7
This demonstrates that retatrutide is more potent at human GIP receptors and less potent at GLP-1 and human glucagon receptors.6,7
Retatrutide activates the GIP, GLP-1, and glucagon receptors. Preclinical and early phase clinical data suggests retatrutide may
See VIDEO LINK: Retatrutide: Mechanism of Action for a video illustrating the mechanism of action of retatrutide.
References
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
1Capozzi ME, DiMarchi RD, Tschöp MH, et al. Targeting the incretin/glucagon system with triagonists to treat diabetes. Endocr Rev. 2018;39(5):719-738. https://doi.org/10.1210/er.2018-00117
2Hædersdal S, Andersen A, Knop FK, Vilsbøll T. Revisiting the role of glucagon in health, diabetes mellitus and other metabolic diseases. Nat Rev Endocrinol. 2023;19(6):321-335. https://dx.doi.org/10.1038/s41574-023-00817-4
3Gribble FM. The gut endocrine system as a coordinator of postprandial nutrient homoeostasis. Proc Nutr Soc. 2012;71(4):456-462. https://doi.org/10.1017/S0029665112000705
4Jakubowska A, Roux CWL, Viljoen A. The road towards triple agonists: glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide and glucagon receptor - an update. Endocrinol Metab (Seoul). 2024;39(1):12-22. https://doi.org/10.3803/EnM.2024.1942
5Hammoud R, Drucker DJ. Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1. Nat Rev Endocrinol. 2023;19(4):201-216. https://doi.org/10.1038/s41574-022-00783-3
6Coskun T, Urva S, Roell WC, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: from discovery to clinical proof of concept. Cell Metab. 2022;34(9):1234-1247. https://doi.org/10.1016/j.cmet.2022.07.013
7Urva S, Du Y, Thomas MK, et al. Novel GIP/GLP-1/glucagon receptor agonist LY3437943: a first in human dose study in healthy participants. Abstract presented at: 81st American Diabetes Association; June 25-29, 2021; Washington, DC, USA.
8Nogueiras R, Nauck MA, Tschöp MH. Gut hormone co-agonists for the treatment of obesity: from bench to bedside. Nat Metab. 2023;5(6):933-944. https://doi.org/10.1038/s42255-023-00812-z
9Jastreboff AM, Kaplan LM, Frías JP, et al. Triple–hormone-receptor agonist retatrutide for obesity — a phase 2 trial. N Engl J Med. 2023;389(6):514-526. https://doi.org/10.1056/NEJMoa2301972
10Kusminski CM, Perez-Tilve D, Müller TD, et al. Transforming obesity: the advancement of multi-receptor drugs. Cell. 2024;187(15):3829-3853. https://doi.org/10.1016/j.cell.2024.06.003
11Rosenstock J, Frías J, Jastreboff A, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet. 2023;402(10401):529-544. https://doi.org/10.1016/S0140-6736(23)01053-X
12Thomas MK, Coskun T, Hartman ML, et al. Retatrutide, an agonist of GIP, GLP-1, and glucagon receptors, improves pancreatic beta cell function and insulin sensitivity. Poster presented at: 84th Annual Scientific Sessions of the American Diabetes Association; June 21-24, 2024; Orlando, FL, USA.
13Ruotolo G, Harris C, Lin Y, et al. A triple GIP, GLP-1 and glucagon receptor agonist, retatrutide, was associated with decreased inflammatory CV risk biomarkers in people with overweight or obesity, with or without type 2 diabetes. Poster presented at: 60th Annual Meeting of the European Association for the Study of Diabetes; September 9-13, 2024; Madrid, Spain.
14Medicines in development. Eli Lilly and Company. Clinical Development Pipeline website. Accessed October 6, 2025. https://www.lilly.com/science/research-development/pipeline
15Giblin K, Kaplan LM, Somers VK, et al. Retatrutide for the treatment of obesity, obstructive sleep apnea, and knee osteoarthritis: Rationale and design of the TRIUMPH registrational clinical trials. Diabetes Obes Metab. Published online October 15, 2025. https://doi.org/10.1111/dom.70209
Date of Last Review: October 06, 2025